Summary Messenger RNAs are typically thought of as passive carriers of genetic information that are acted upon by protein- or small RNA-regulatory factors and by ribosomes during the process of translation. We have discovered that the 5- untranslated regions (UTRs) of numerous bacterial mRNAs serve a more proactive role in metabolic monitoring and genetic control. RNA genetic switches called riboswitches selectively bind metabolites without the need for proteins, and subsequently modulate gene expression by several distinct mechanisms. Riboswitches exhibit striking complexity in structure and action, and our findings indicate that cells from all three domains of life use these metabolite-sensing RNAs to control fundamental metabolic pathways. Furthermore, we have evidence that riboswitches can be targeted with small compounds that disregulate gene expression and thereby function as antibiotics. We will establish the basic functions of ?orphan? riboswitches whose ligands remain mysterious. Particular emphasis will be focused on the most widespread classes of these noncoding RNAs such that our discoveries will have the greatest impact on improving our understanding of bacterial pathogens. We will also validate the functions of several new ribozyme classes. These analyses of the structural and functional characteristics of novel riboswitch and ribozyme systems are intended to establish the basic principles of riboswitch molecular recognition and function. Our findings will increase our understanding of bacterial gene control mechanisms, facilitate atomic-resolution structural analyses of riboswitch and ribozyme RNAs, and provide new targets for antimicrobial drug development.